title: A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population.
abstract: CYP4A11 oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite with renovascular and tubular function in humans. A previous study demonstrated a significant association between the CYP4A11 gene polymorphism and hypertension; however, the precise mechanism of the association has not been clarified. To assess the involvement of CYP4A11 in the pathogenesis of hypertension, we sought to identify a functional polymorphism of CYP4A11 and examined its impact on predisposition to hypertension in the Tanno-Sobetsu Study. The -845A/G polymorphism was identified in the promoter region of CYP4A11 by direct sequencing. Luciferase expression driven by the promoter of CYP4A11 containing the wild-type -845GG genotype was 30% lower than expression with the variant -845AA genotype. Gel mobility shift assays with nuclear protein extracts showed specific binding to probes containing the variant -845GG. To assess the effect of CYP4A11 polymorphisms on hypertension, we also carried out a case-control study using 4 single nucleotide polymorphisms (-845A/G, -366C/T, 7119C/T, and 8590T/C) in the Tanno-Sobetsu Study. The odds ratio for hypertension in participants with the AG+GG genotype of -845A/G was 1.42 (P=0.008), and the odds ratio for hypertension of the TT genotype of 7119C/T was 1.37 (P=0.037) after adjusting for confounding factors. The haplotype-based case-control analysis using 4 single nucleotide polymorphisms revealed a significant haplotype (G-C-T-T) that was significantly associated with hypertension, with an odds ratio of 1.44 (P=0.006) after adjusting for confounding factors. We have identified a functional variant (-845A/G) of CYP4A11 that is significantly associated with hypertension and that appears to be a novel candidate for a predisposing factor for hypertension.
authors.affiliation: Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akasaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Izumi
authors.initials: I
authors.lastname: Shimaoka
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data*; D016022:Case-Control Studies; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000208:ethnology* / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D003577:Cytochrome P-450 Enzyme System; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A